Dengue viruses (DENV) are the most prevalent arthropod-borne viral pathogens infecting humans. These mosquito-transmitted viruses, members of the Flaviviridae, are endemic to most tropical and sub-tropical countries with nearly half of the world's population living at risk of DENV infection and resulting in over a million estimated infections annually (Mackenzie et al., Nat Med 10:S98-109, 2004; Gubler, Arch Med Res 33:330-342, 2002). Infection with DENV can cause a broad range of symptoms, ranging from subclinical, to the self-limiting flu-like illness dengue fever (DF), to the more severe and life-threatening dengue hemorrhagic fever and shock syndrome (DHF/DSS) characterized by increased vascular permeability producing plasma leakage, severe thrombocytopenia and hypotension leading to circulatory collapse (Gubler, Novartis Found Symp 277:3-16; discussion 16-22, 71-13, 251-253, 2006). DENV prevalence, infection rates, and disease severity have increased exponentially since the middle of the last century (Guzman et al., Nat Rev Microbiol 8:S7-S16, 2010). Despite decades of interest, need, and effort there remains no available dengue vaccine and vaccine candidates continue to run into roadblocks and safety concerns both in pre-clinical development and in clinical trials (Guy et al., Hum Vaccin 6(9), Epub Sep. 16, 2010; Miller, Curr Opin Mol Ther 12:31-38, 2010; Thomas, J Infect Dis 203:299-303, 2011; Murphy and Whitehead, Annu Rev Immunol 29:587-619, 2011).
Dengue vaccine development is plagued by a number of biological and immunological challenges that also affect vaccinology for other multi-strain pathogens. These include the necessity for a tetravalent vaccine inducing balanced immunity, the lack of an animal model for DENV disease, and concerns regarding vaccine-induced severe DENV pathology (Murphy and Whitehead, Annu Rev Immunol 29:587-619, 2011; Morens and Fauci, JAMA 299:214-216, 2008). DENV immune responses are both protective and pathogenic and it is this duality that directly impedes vaccine development (Rothman, J Clin Invest 113:946-951, 2004). There are four closely related yet phylogenetically distinct DENV serotypes (DENV-1, -2, -3, and -4) and infection with any one serotype appears to induce life-long serotype-specific immunity, yet cross-protection between serotypes is limited and transient (Sabin, Am J Trop Med Hyg 1:30-50, 1952; Kuno, Adv Virus Res 61:3-65, 2033). Thus, in endemic regions individuals are susceptible to up to four different DENV infections.
Although there are a number of risk factors associated with DHF such as virus and host genetics, by far the strongest risk factor for severe dengue pathology is secondary infection with a previously unencountered (heterologous) serotype (Murphy and Whitehead, Annu Rev Immunol 29:587-619, 2011). This association explains the exponential increase of DHF/DSS in recent decades as co-circulation and simultaneous transmission of the four DENV serotypes increases both temporally and geographically (Mackenzie et al., Nat Med 10:S98-109, 2004; Gubler, Novartis Found Symp 277:3-16; Guzman et al., Nat Rev Microbiol 8:S7-S16, 2010). In humans, increasing viral load correlates with DENV disease severity and a large body of evidence points to the importance of immune enhancement being a causal factor for the increased viral loads associated with DHF (Vaughn et al., J Infect Dis 181:2-9, 2000; Libraty et al., J Infect Dis 185:1213-1221, 2002).